N-(cyclic aminomethyl) phenylpiperidyl-methanes and carbinols



United States Pateflt N-(CYCLHJ AMINOMETHYL) PHENYLPIPERIDYL- METHANESAND CARBINOLS Kurt J. Rorig, Glenview, ]ll., assignor to G. D. Searle 85Co., Chicago, Ill., a. corporation of Delaware No Drawing. ApplicationDecember 31, 1956 Serial No. 631,394

7 Claims. (Cl. 260-2943) This invention relates to N-(cyclicaminomethyl) phenylpiperidylmethanes and carbinols, and to processes forthe manufacture thereof. More particularly, this in: vention relates tocompounds of the formula hydrogen or a hydroxyl radical, and Z ishydrogenor a phenylradical. Among the oxygenated cyclic amino groupingscontemplated by R in the foregoing formula, those comprising 4 or 5carbon atoms in a fully saturated nitrogen heterocycle substituted by atleast 1 oxygen atom and optionally alkylated or condensed with a benzenering, are preferred. Examples of such radicals are the succinimido,phthalimido, and B-ethyl-fl-methylglutar-- imido groupings.

The compounds to which this invention relates are useful because oftheir valu ble pharmacological properties. Especially, the subjectcompounds manifest central associative effects in mammals, being adaptedto the control of apomorphine-induced nausea, and the potentiatior ofbarbiturate sedation.

Manufacture of the claimed compounds is accomplished by heatinganappropriate benzylpiperidine, benzhydrylpiperidine, phenylpiperidylcarbinol, or diphenylpiperidyl carbinol, as indicated, with an imide,RH, in the presence of formalin, using an alcoholic reaction medium.Synthesis is ordinarily complete in from). to 8 hours when boilingethanol is the medium of choice.

The following examples describe in detail certain of the compoundsillustrative of the present inventionaud methods which have been devisedfor their preparation. However, the invention is not toybe construedaslimited thereby, either in spirit or in scope, since itwill 'beapparent to those skilled in the art of organic synthesis that manymodifications, both of, materials and of methods, may be practicedwithout departing from the'purpose and intent of this disclosure. In theexamples hereinafter detailed, temperatures are given in degreescentigrade 6Q benz 1 i -idi and relative amouts of materials in parts byweight, except as otherwise noted.

Example 1 Phenyl 4 (N -succinimidomethylpiperidyl) carbin0l.--

2,833,??? Patented May 5, 1958 ice with hexane. The product thusobtained is phenyl-4-(N- succinimidomethylpiperidyl)carbinol, of theformula Example 2 I Phenyl-l-(Nphthcilin'iidomethylpiperidyl)carbinol.-- Apmixture of 8 parts ofphenyl-4-piperidylcarbinol, 9

parts of-phthalimide, 12 parts of formalin and 70 parts 0 .ofabsoluteethanol is heated at 90-100 C. for 2 hours, 1 then filtered hot andrefrigerated. There precipitates from the filtrate purephenyl-4-(N-phthaliniidomethylpiperidyl)carbinol, .a white powdermelting at 168-.170" C. The product has the formula Example 3 2-[N-(p-ethyl-p methylglu arimidomethyl)piperidyl]- 40 phenylmetlmne.-Amixture of approximately 6 parts of t p-ethylafi-methylglutarimide, 80parts of absolute-ethanol,

. andilz parts offormalin is heated to-homogeneity, folrlowing'ivhichtherezis added 7 parts of Z-berlzylpiperidine.

' .T he reactants are then heated at 90-100" Q under reflux for *2hours,v whereupon they are filtered and cooled. Upon introductionof 40parts of water, 2- [N-(p-ethyl-flmethyl glutarimidomethyl)piperidyl]phenylm e t h an e is thrown out of solution. The product has theformula In a similar manner, 4-[N-(B-ethyl-p-methylglutarimidomethyl)piperidyl]phenylmethane isprepared from 4- Example 4 Diphenyl 4 (N succinimidomethylpiperidyl)methane.-To a warm solution of 3 parts of 'succinimide in a 5 mixture of65 parts of absolute ethanol and 6 parts of .formalinis added 5 parts of4-benz hydrylpiperidine.- The iresjultanpmixture isheated at the boilingpoint .under reflux-for 2% hours. Approximately 40 parts of water is I.then introduced, following which, on'cooling, there is precipitatedWhite crystals of diphe methylpiperidyl)methane. The product thusobtained,

y1 4-(N-succinimidomelts at l83.5-l85.5"

, arm-The following point under reflux nol.To a solution ofrecrystallized from approximately 55 parts of methanol, C. The producthas the formula Example 5 Diphenyl 4 (N-silccin'imidomethylpiperidyl)c ar b i nol. To a solution of 3 parts of absolute ethanol and 6 parts offormalin is added ap'proximatelyS parts of diphenyl-4-piperidylcarbinol.The reactants are heated at 90100 C. under reflux for 3 hours, thendiluted with 50. parts of warm water, tate. The 'powdery white materialthrown down is diphenyl-4-(N-succinimidomethylpiperidyl) carbinol, whichmelts at approximately 184.5-185.5 C. The Product has the formula m t Va cll rN N Example 6 Diphenyl 4 (N 9 phthalimidomethylpiperidyl)methreactants are heated at the boiling for. eight hours: 2 parts of4-benzhydrylpiperidine, 2 parts of phthalimide, 2 parts of formalin, and20 parts of absolute ethanol. There is then introduced an additionaLlSparts of absolute ethanol, whereupon the mixture is reheated to theboiling point andtiltered hot. From the; filtrate, on chilling, there ismethylpiperidyl)methane, M. P. 187-188" C., which has the formula BIN at Ejxample7 V V Diphenyl -4 (N phthalimidomthylpiperidyl)carbi- 7 partsof phthalimide in approximately 120 parts of absolute ethanolis added 10parts of formalin and approximately 7 partsjof diphenyl-4-piperi-'filtered, and chilled to precipi- 90 C. under reflux for 2% hours. Onchilling, there is precipitateddiphenyl-4-(N-phthalirnidomethylpiperidyl)- carbinol, which, separatedand recrystallized from approximately 400 parts of methanol, is obtainedas fine white needles melting at 178-180" C. The product has the formulaExample 8 r 4-[N-(fi-ethyl-flmelhylglutarimidomethyl)piperia'ylldiphenylmethana-A mixture of 5 partsof fl-ethyl-pmethylglutarimide, 40 parts of absolute ethanol, and 6parts of formalin is heated to homogeneity, following which there isadded 5 parts of 4-benzhydrylpiperidine. The reactants are then heatedat 90400 C. under reflux for 2hours, filtered, and finally refrigerated.On prolonged standing, there precipitates clear rhomboidal crystals of4-[N-(fl-ethyl-p-methylglutarimidomethyl)piperidylldiphenylmethane,which may be further purified by I sublimation; The product has theformula 7 60 which melt at 17 18 CHzN Example, 9

4- [N ,B-ethyl t3 met/1ylglutal-fmiaionzethyl)piperidyl] h dylcarbinol.The resultant solution is heated at about What is claimed is: 1. Acompound of the formula N-CHaR phthalimidomethylpip eridyl) carcompoundsof N-CHaR 6 wherein R is selected from the group consisting ofsuccinimido, phthalimido, and fi-ethyl-fl-methylglutarimido radicals, Xis selected from the group consisting of hydrogen and hydroxyl radicals,and Z is selected from the group consisting of hydrogen and phenylradicals, the step which comprises heating a compound of the formulawherein X and Z are defined as before, with an imide or of the formula Rbeing defined as before, in the presence of formalin,

using an alcoholic reaction medium.

6. Diphenyl 4 (N phthalimidomethylpiperidyl)- methane.

7. 4 [N (,8 ethyl B methylglutarimidomethyl)- piperidyl]-diphenylcarbinol.

No references cited.

1. A COMPOUND OF THE FORMULA 